A Double Jeopardy: Loss of FMRP Results in DSB and Down-regulated DNA Repair.
A Double Jeopardy: Loss of FMRP Results in DSB and Down-regulated DNA Repair.
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发表时间：
2022
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通讯作者：
Feng W
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作者：
Chakraborty A;Grageda A;Kuznetsov VA;Feng W
我们对核细胞质 FMRP 蛋白分子功能的理解主要围绕其参与细胞质中的蛋白质翻译调节，如果该蛋白缺失或功能失调，则会导致脆性 X 综合征 (FXS)。最近的研究已经开始研究 FMRP 的核和基因组功能。我们已经证明，在 DNA 复制应激期间，FXS 患者来源的细胞维持 R 环形成和 DNA 双链断裂水平增加。在这里，我们描述了这些细胞的转录组分析，以确定那些在有或没有复制压力的情况下受 FMRP 丢失影响最大的基因。我们发现 FMRP 丢失会导致先前在未经治疗的条件下报道的转录组变化。重要的是，我们还表明，复制应激除了导致 DSB 过量外，还会导致几乎所有 DNA 修复途径的转录下调。这一发现表明，尽管 DNA 损伤反应正常，但 FXS 患者来源的细胞会经历 R 环诱导的 DNA 断裂以及 DNA 修复功能受损，这实际上是双重危险。我们建议，必须加深对 FMRP 核功能，特别是基因组保护功能的理解，这将导致 FXS 新型治疗干预措施的发现。
Our understanding of the molecular functions of the nucleocytoplasmic FMRP protein, which, if absent or dysfunctional, causes the fragile X syndrome (FXS), largely revolves around its involvement in protein translation regulation in the cytoplasm. Recent studies have begun honing in on the nuclear and genomic functions of FMRP. We have shown that during DNA replication stress, cells derived from FXS patients sustain increased level of R-loop formation and DNA double strand breaks. Here, we describe a transcriptomic analysis of these cells in order to identify those genes most impacted by the loss of FMRP with and without replication stress. We show that FMRP loss causes transcriptomic changes previously reported in untreated conditions. Importantly, we also show that replication stress, in addition to causing excess of DSB, results in down-regulation of transcription in virtually all DNA repair pathways. This finding suggests that despite normal DNA damage response, FXS patient-derived cells experience R-loop-induced DNA breakage as well as impaired DNA repair functions, effectively a double jeopardy. We suggest that it is imperative to deepen the understanding of the nuclear functions, particularly a genome protective function, of FMRP, which will lead to discoveries of novel therapeutic interventions for the FXS.